Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma
Anna K. Scherger, … , Stefan Rose-John, Ulrich Keller
Anna K. Scherger, … , Stefan Rose-John, Ulrich Keller
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e128435. https://doi.org/10.1172/jci.insight.128435.
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Research Article Oncology

Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma

Abstract

Aberrant activity of the glycoprotein 130 130/JAK/STAT3 (gp130/JAK/STAT3) signaling axis is a recurrent event in inflammation and cancer. In particular, it is associated with a wide range of hematological malignancies, including multiple myeloma and leukemia. Novel targeted therapies have only been successful for some subtypes of these malignancies, underlining the need for developing robust mouse models to better dissect the role of this pathway in specific tumorigenic processes. Here, we investigated the role of selective gp130/JAK/STAT3 activation by generating a conditional mouse model. This model targeted constitutively active, cell-autonomous gp130 activity to B cells, as well as to the entire hematopoietic system. We found that regardless of the timing of activation in B cells, constitutively active gp130 signaling resulted in the formation specifically of mature B cell lymphomas and plasma cell disorders with full penetrance, only with different latencies, where infiltrating CD138+ cells were a dominant feature in every tumor. Furthermore, constitutively active gp130 signaling in all adult hematopoietic cells also led to the development specifically of largely mature, aggressive B cell cancers, again with a high penetrance of CD138+ tumors. Importantly, gp130 activity abrogated the differentiation block induced by a B cell–targeted Myc transgene and resulted in a complete penetrance of the gp130-associated, CD138+, mature B cell lymphoma phenotype. Thus, gp130 signaling selectively provides a strong growth and differentiation advantage for mature B cells and directs lymphomagenesis specifically toward terminally differentiated B cell cancers.

Authors

Anna K. Scherger, Mona Al-Maarri, Hans Carlo Maurer, Markus Schick, Sabine Maurer, Rupert Öllinger, Irene Gonzalez-Menendez, Manuela Martella, Markus Thaler, Konstanze Pechloff, Katja Steiger, Sandrine Sander, Jürgen Ruland, Roland Rad, Leticia Quintanilla-Martinez, Frank T. Wunderlich, Stefan Rose-John, Ulrich Keller

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Figure 4

gp130 activation during or after GC B cell differentiation results in lymphoma and plasmacytoma.

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gp130 activation during or after GC B cell differentiation results in ly...
(A) Kaplan-Meier curve showing survival of Cγ1 L-gp mice (n = 50) in comparison with Cγ1 (n = 7) and L-gp (n = 12) controls. The median survival of Cγ1 L-gp compound mice was 629 days. Controls did not show any signs of malignancy during the observed time frame (*P = 0.0109, Mantel-Cox test). (B) Kaplan-Meier curve showing survival of Blimp1 L-gp mice (n = 19) in comparison with Blimp1 (n = 11) and L-gp (n = 12) controls. The median survival of Blimp1 L-gp mice was 329 days. Controls did not show any signs of disease during the observed time frame (****P < 0.0001, Mantel-Cox test). (C) Flow cytometric analysis from mesenteric nodal tumors of diseased Cγ1 L-gp mice identified 3 cohorts: CD19−CD138+ (PC, left), CD19+IgD+ mature B cell (Mature, middle), and CD19+GL7+ GC B cells (GC, right). Shown is the analysis of mesenteric nodal tumor material from 1 representative animal per phenotype. At least 3 mice per group were analyzed. (D) Distribution of the 3 types of B cell malignancies in diseased Cγ1 L-gp mice. (E) Flow cytometric analysis from diseased Blimp1 L-gp mice identified a CD19−CD138+ (PC) phenotype (left) and a CD19+IgD+ mature B cell phenotype (Mature, right). Shown is the analysis of mesenteric nodal tumor material from 1 representative animal per phenotype. At least 3 mice per phenotype were analyzed. (F) Distribution of the 2 types of B cell malignancies in diseased Blimp1 L-gp mice. (G) Histological and immunohistochemical analysis of 1 representative mesenteric nodal tumor from Blimp1 L-gp (left) and Cγ1 L-gp (middle and right) mice. Tumors with the PC phenotype showed high infiltration of malignant cells positive for CD138 (left and middle). The GC phenotype displays only minor infiltration of CD138+ cells (right). At least 3 mice per genotype were analyzed. Original magnification, ×400.